title: Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules.
abstract: The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)(exp)). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)(exp) and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)(exp). This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)(exp) and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Scripps Florida, 130 Scripps Way #3A1, Jupiter, Florida 33458, USA.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Childs-Disney
authors.forename: Ewa
authors.initials: E
authors.lastname: Stepniak-Konieczna
authors.forename: Tuan
authors.initials: T
authors.lastname: Tran
authors.forename: Ilyas
authors.initials: I
authors.lastname: Yildirim
authors.forename: HaJeung
authors.initials: H
authors.lastname: Park
authors.forename: Catherine Z
authors.initials: CZ
authors.lastname: Chen
authors.forename: Jason
authors.initials: J
authors.lastname: Hoskins
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Chris P
authors.initials: CP
authors.lastname: Austin
authors.forename: George C
authors.initials: GC
authors.lastname: Schatz
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sobczak
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
mesh_terms: D000818:Animals; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000188:drug therapy* / Q000235:genetics*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects; D012313:RNA / Q000378:metabolism; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C493663:MBNL1 protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; D012313:RNA; D011972:Receptor, Insulin